The present invention relates to methods of synthesizing polymeric compounds, and more particularly, to methods of synthesizing polymeric compounds comprising polyethylene glycol moieties.
Polyethylene glycol (PEG) is used in a wide variety of applications including, but not limited to, plasticizers, softeners, humectants, ointments, polishes, paper coating, mold lubricants, bases for cosmetics and pharmaceuticals, solvents, binders, metal and rubber processing, and additives to foods and animal feed. Some particular uses of PEG in pharmaceutical applications include, for example, formation of PEG-drug conjugates, treatment of neonatal respiratory distress syndrome, treatment of functional and/or chronic constipation, treatment of encopresis in children, and diagnosis and therapy of gastrointestinal diseases.
PEG is typically produced by base-catalyzed ring-opening polymerization of ethylene oxide. The reaction is initiated by adding ethylene oxide to ethylene glycol, with potassium hydroxide as catalyst. This process results in a polydispersed mixture of polyethylene glycol polymers having a molecular weight within a given range of molecular weights. For example, PEG products offered by Sigma-Aldrich of Milwaukee, Wis. are provided in polydispersed mixtures such as PEG 400 (Mn 380-420); PEG 1,000 (Mn 950-1,050); PEG 1,500 (Mn 1,400-1,600); and PEG 2,000 (Mn 1,900-2,200).
In J. Milton Harris, Laboratory Synthesis of Polyethylene Glycol Derivatives, 25(3) Rev. Macromol. Chem. Phys. 325-373 (1985), the author discusses synthesis of monomethyl ethers of PEG (also known as methyl-terminated PEG or mPEG). The reference states that mPEG contains a significant amount (as much as 25%; from size exclusion chromatography) of PEG without the methoxy end group. This PEG xe2x80x9cimpurityxe2x80x9d may result from water present in the polymerization process. Under basic conditions, hydroxide is produced, which yields PEG upon reaction with the ethylene oxide monomer. Since the hydroxide-initiated PEG chain can grow at both ends, while the methoxide-initiated chain can grow from only one end, the resulting mixture has a broader molecular weight distribution than that for the PEG""s.
While these polydispersed mixtures of PEGs and/or mPEGs may be useful for some applications, physical properties of polymers may vary with the length of the polymer. Thus, polydispersed mixtures may not be suitable for certain applications that require specific physical properties. Additionally, the heterogeneity of commercially available PEGs and mPEGs may complicate spectroscopic analysis, physico-chemical characterization and pharmacokinetics analysis. As a result, it is desirable to provide monodispersed mixtures of PEGs and/or mPEGs.
Monodispersed mixtures of PEG and/or mPEG polymers may be provided by various organic synthesis routes. For example, in Yiyan Chen and Gregory L. Baker, Synthesis and Properties of ABA Amphiphiles, 64 J. Org. Chem. 6870-6873 (1999), the authors propose the following scheme: 
This synthesis route may be inconvenient due to the number of steps required as well as the use of undesirable reaction conditions such as high temperatures that may actually break down the PEG polymer. Moreover, it may be difficult to purify the product as the starting material may always be present in the reaction mixture.
In Gxc3xa9rard Coudert et al., A Novel, Unequivocal Synthesis of Polyethylene Glycols, Synthetic Communications, 16(1): 19-26 (1986), the authors proposed the following synthesis route: 
This synthesis route may be inconvenient due to the undesirable reaction conditions, which do not lead to mPEG.
As a result, it is desirable to provide a new route for synthesizing PEG, mPEG, and/or polymers comprising a PEG moiety that are more efficient and do not require such undesirable reaction conditions.
Embodiments of the present invention provide improved methods for synthesizing substantially monodispersed mixtures of polymers comprising polyethylene glycol moieties. Methods according to embodiments of the present invention may utilize reaction conditions that are milder than those required by the conventional methods described above. For example, many, if not all, of the steps of methods according to embodiments of the present invention may be carried out at atmospheric pressure and/or at room temperature. The ability to perform these steps at atmospheric pressure and/or temperature may reduce or prevent the formation of undesirable side products. Additionally, methods according to embodiments of the present invention may be more efficient than the conventional methods described above. For example, methods according to embodiments of the present invention may require fewer steps and/or less time than the conventional methods described above. Methods according to embodiments of the present invention may provide the ability to remove PEG starting materials from the products comprising polyethylene glycol moieties to provide substantially monodispersed mixtures of polymers comprising polyethylene glycol moieties.
According to embodiments of the present invention, a method of synthesizing a substantially monodispersed mixture of polymers comprising polyethylene glycol moieties includes:
reacting a substantially monodispersed mixture of compounds having the structure of Formula I:
R1(OC2H4)nxe2x80x94Oxe2x88x92X+xe2x80x83xe2x80x83(I)
wherein R1 is H or a lipophilic moiety; n is from 1 to 25; and X+ a positive ion,
xe2x80x83with a substantially monodispersed mixture of compounds having the structure of Formula II:
R2(OC2H4)mxe2x80x94OMsxe2x80x83xe2x80x83(II)
wherein R2 is H or a lipophilic moiety; and m is from 1 to 25, under conditions sufficient to provide a substantially monodispersed mixture of polymers comprising polyethylene glycol moieties and having the structure of Formula III:
R2(OC2H4)m+nxe2x80x94OR1xe2x80x83xe2x80x83(III).
Methods according to embodiments of the present invention may provide more efficient synthesis routes for substantially monodispersed mixtures of PEGs, substantially monodispersed mixtures of mPEGs and/or substantially monodispersed mixtures of polymers comprising PEG moieties. Methods of the present invention may reduce the number of steps and/or reduce the overall synthesis time compared to conventional methods of synthesizing PEG polymers. Methods of the present invention may also utilize milder reaction conditions than those used in conventional methods.